In June 2003, the House of Commons Standing Committee on Health agreed to a study on prescription drugs (patented and generic) in Canada. Through a primary focus on the health aspects, it undertook to examine costs; price controls; drug approvals; adverse drug reactions; prescribing practices; marketing to and lobbying of prescribers and dispensers; direct-to-consumer advertising; access to drugs; and, misuse, abuse and addiction within the general population.
Over two months in the fall of 2003, the Health Committee held extensive hearings on the health-related aspects of prescription drugs. In addition to frequent meetings in Ottawa, the Committee travelled to western and eastern destinations to listen to the views of Canadians. This work produced a rich body of evidence and revealed multiple issues of shared concern.
This first report addresses three key issues relevant to prescription drugs in Canada: clinical trials, post-market surveillance and direct-to-consumer advertising. Building on information provided by witnesses, the report focuses on the federal responsibility in each area. The Committee intends to produce a second report on other areas of concern identified during our meetings across Canada.
Key to the work of this committee is its understanding that drugs are an integral part of the Canadian health care system and that the appropriate use of prescription drugs continues to benefit individuals across the country. However, it also recognizes the challenges of ensuring equitable access to safe, effective, quality drugs while managing costs. This report is the initial step in the work of assessing the health-related aspects of many issues related to prescriptions drugs. One objective is to increase public access to information about the realm of prescription drugs.
KEY ISSUES FOR CANADIANS
What We Heard
In the process of drug development, clinical trial research is essential to provide scientific data on a drug’s safety, efficacy and optimal dosage. Clinical trials involve direct observation of human subjects. Health Canada then uses the data to evaluate a company’s application for marketing a product for human use.
In Canada, regulatory requirements for clinical trials on drugs were developed in the 1960s. In 2001, changes to the regulations included an emphasis on the importance of research ethics boards and the establishment of a new inspection program. In general, a drug sponsor applies to Health Canada for authorization to conduct a clinical trial. The application must contain documents, including a copy of the protocol and a copy of the statement, to be set out in each informed consent form, about potential risks and anticipated benefits. Prior approval by a research ethics board is not required when making an application. However, prior to the commencement of a trial, the sponsor must identify the research ethics board and obtain research ethic board approval for the clinical trial protocol and for the informed consent form. After the clinical trial is initiated, inspections by Health Canada verify compliance with the regulatory requirements.
When approved, clinical trials are normally carried out in three phases. Phase 1 trials assess drug safety and involve a small number of adult volunteers. Phase 2 trials assess drug efficacy and recruit several hundred individuals randomly divided into a treatment group and a control group. Phase 3 trials assess drug efficacy, benefits and adverse reactions and require a very large group, possibly thousands of individuals, organized to be randomized, blinded, and long‑term. Some witnesses called for federal regulatory requirements for a fourth phase or a phase 4 trial for additional assessment after the drug is available on the market.
Witnesses pointed to uneven standards and inconsistent operations among research ethics boards across the country. Currently, research ethics boards are not subject to federal regulations. Witnesses expressed concern about the lack of a standard accreditation system or regular audits for research ethics boards. Presently, the Canadian Institutes of Health Research expects funding recipients to adhere to the Tri-Council Policy Statement on ethical conduct for research involving humans. In addition, the National Council on Ethics in Human Research, a voluntary body made up of representatives from key organizations in clinical research and from the public, assists research ethics boards in interpreting and implementing guidelines for the ethics of research involving human subjects. However, there is no single national body mandated to provide oversight for the ethical conduct of human research in either the public or private sector.
Witnesses had strong views about the lack of transparency associated with clinical trials. Overall, the concerns focused on the fact that, although the data generated from the various phases may be viewed by Health Canada and is sometimes included in published scientific and clinical reports, most of it remains confidential and unavailable to the individuals using the products. The drug companies argue that confidentiality is essential to limit the acquisition of knowledge by their competitors. To ensure this, the companies may require researchers, coordinators and others involved in clinical trials to sign confidentiality agreements. Several witnesses suggested that the confidentiality requirements meant that questionable activities went unreported due to fears about retaliation. They urged Health Canada to enhance its inspection process and to consider ways of legally protecting clinical trial researchers and other staff if they reported information deemed confidential. Witnesses pointed out that the confidentiality requirement left no avenue for Canadians to assess the completeness of the data used by the regulator, the reliability of the submitted information or the decision‑making process leading to product availability. Individuals who use the resulting drug and who may suffer adverse effects as well as the prescribing physicians have difficulty accessing relevant data from the clinical trials.
Witnesses also questioned the increased reliance on partnerships between the pharmaceutical industry and university research centres and the lack of independence for individual researchers. Some witnesses expressed concerns about the trend to commercially oriented research organizations outside of academic centres. It was pointed out that companies developing a product and funding trials not only have the dominant role in designing protocols and choosing investigators, but they also play a major role in selecting volunteers as well as collating and interpreting the data. In addition to these areas where there is a strong potential for conflict of interest, companies have final approval over publication and usually seek positive reports published in established medical journals to raise awareness of their products and to promote their use.
The Health Products and Food Branch Inspectorate recently conducted inspections to validate data collected in the conduct of clinical trials as well as to increase the protection of enrolled subjects. A July 2003 report titled Summary Report of the Inspections of Clinical Trials Conducted Under the Voluntary Phase observed a number of deficiencies in areas related to records, to accuracy, to completeness and maintenance of source data, to systems and procedures for processes, and to informed consent forms for subjects enrolled in clinical trials.
What We Think
The Health Committee believes that the health and safety of individuals who participate in clinical trials must be paramount. While it supports the current regulatory framework, it wants further measures to ensure that Canadians are not exposed to any undue risks during clinical drug trials. It calls for more rigorous scrutiny of clinical trial applications and an increase in the number of inspections.
The Committee does not support a clinical trial system that discourages openness in order to protect commercial interests. It feels that individual Canadians may be harmed by the lack of scrutiny and by a dearth of independently assessed information. It calls for increased transparency for Canadians and more accountability by Health Canada. To this end, it supports the development of mechanisms to enable public disclosure of information about clinical trials without jeopardizing either the intellectual property rights of drug companies or the privacy of individuals involved in the clinical trials.
The Committee strongly supports the development of accreditation and oversight for research ethics boards responsible for assessing clinical trials. It also wants a full and open public discussion about confidentiality agreements that currently prevent disclosure concerning negative outcomes in clinical trials. In particular, it feels that information on all serious adverse drug reactions observed during clinical trials and reported to Health Canada should be made publicly available.
The Committee therefore recommends that:
· Health Canada significantly increase the number of inspections conducted annually for all phases of all current clinical trials for prescription drugs involving human subjects and produce public annual reports of the findings;
· Health Canada introduce measures to ensure public confidence in the clinical trial process, starting with a public database that provides information on trials in progress, trials abandoned and trials completed;
· Health Canada develop standards that establish an accreditation process for research ethics boards assessing clinical trials;
· Health Canada conduct consultations aimed at discouraging or at least minimizing the use of confidentiality agreements when conducting clinical trials.
What we heard
The Marketed Health Products Directorate of the Health Products and Food Branch is responsible for post-market assessment and surveillance of therapeutic health products (pharmaceutical drugs and medical devices). Post-market surveillance involves a complex set of activities with the objective of identifying or further clarifying risks and therapeutic effectiveness of the products once they are in the Canadian marketplace. These post-market surveillance activities are a shared responsibility of manufacturers, health professionals, researchers, and regulators and require ongoing consultation and collaboration among the various stakeholders.
Currently, Health Canada relies on voluntary reporting of adverse drug reactions from physicians, pharmacists or patients and mandatory reporting from drug manufacturers. The Department administers five adverse reaction regional centres (situated in British Columbia, Saskatchewan, Ontario, Quebec, Nova Scotia) as well as a national centre in Ottawa. The national centre has eight Adverse Reaction Information specialists and each regional centre has one professional coordinator. In 2002, the Department received more than 8,500 domestic adverse reaction reports and more than 106,600 foreign adverse reaction reports. There were 169 recalls of drugs for human use for the same year. Health Canada estimated that half of newly approved therapeutic health products have serious side effects identified only after approval and marketing due to exposure within the larger population.
To facilitate surveillance and reporting of adverse drug reactions, Health Canada maintains a Canadian Adverse Drug Reaction Monitoring Program (CADRMP). The CADRMP database contains information from individual reports based on suspicion, opinion or observation. The Department also publishes and distributes a quarterly Canadian Adverse Reaction Newsletter. In addition, it provides access to a toll-free telephone and fax line and to Web site information on adverse reactions. Other departmental measures to provide access to health professionals range from broad-based education using guideline development and conference presentations to individualized computer-based information access.
Despite Health Canada’s efforts, witnesses called for more effective post‑market surveillance in Canada. Health professionals indicated that they rarely take time to fill out the reports and that the forms themselves are difficult to find and to use. Many consumers were unaware of the toll-free number and of their capability to report adverse drug reactions. Generally, consumers suggested that their role is to identify their adverse drug reaction to a healthcare professional, physician or pharmacist.
In the absence of an adequate reporting system, some consumers have established their own databases to record personal experiences with prescription medicines. Some health professionals have set up mechanisms in hospitals to identify and investigate adverse drug reactions. Witnesses provided various estimates of the extent of the problem. It was suggested that up to 50% of hospital patients have an adverse drug reaction, either contributing to their hospitalization or during their hospital stay. One study calculated as many as 10,000 deaths yearly related to in-hospital adverse drug reactions in Canada. Reported adverse reactions could include not only those associated with a particular suspected drug but also negative outcomes associated with inappropriate drug dosages, underlying medical conditions, faulty dispensing and simultaneous use of other medications. Many witnesses argued that adverse drug reactions lead to increased physician and emergency room visits and more hospital stays, with a significant effect on overall health care costs in Canada.
Both health professionals and consumers called on Health Canada for increased monitoring of submitted adverse reaction reports, collation of the resulting data, and information dissemination. Many witnesses stated that the current monitoring of adverse drug reactions by Health Canada, by health professionals and by manufacturers is inadequate. Some witnesses pointed to the need for Health Canada to improve its communications strategy to better inform health care providers of the least complex way to submit the adverse reaction reports. They wanted simpler electronic means of transmitting information between the Department and health professionals and urged Health Canada to work collaboratively with the Canadian Medical Association and the Canadian Pharmacists Association to achieve this goal. Several witnesses emphasized the need for Health Canada to be more proactive in providing public reports about adverse drug reactions.
Other witnesses called for more fundamental changes. They argued that complete reporting of adverse drug reactions would only take place if it were made mandatory for physicians and pharmacists. They insisted that the pharmaceutical industry should have more extensive mandatory reporting requirements and be required to invest in the post-marketing and adverse reaction reporting process. They suggested the establishment of an independent agency, like the Aviation Safety Board, to investigate drug safety.
What we think
The Committee feels that the current system for post-market surveillance of prescription drugs needs major changes to be effective. It acknowledges that Health Canada is making efforts to facilitate reporting options and to improve its communications and public relations with regard to post-market surveillance. However, additional measures must be taken to make certain that health professionals have ready access to an adverse reaction reporting system that assists rather than discourages their efforts. The Committee is very concerned about the lack of staff resources within the Department to address adverse drug reaction reports and calls for additional resources to assess the reports and to reflect the findings back to health professionals and consumers.
The Committee wants to ensure that the observations made by consumers about adverse drug reactions are taken seriously; that they are reported, recorded, reviewed and made publicly available. The Committee agrees that the current system of voluntary reporting by health professionals and consumers as well as the mandatory reporting by drug manufacturers is unsatisfactory. It sees a need for more comprehensive mandatory reporting by manufacturers and for an extension of mandatory reporting to health professionals. It believes that the number of Canadians affected by adverse reactions to drugs would be reduced if both manufacturers and health professionals were required to forward information to Health Canada on all serious adverse drug reactions within 48 hours of their recognition.
As a further measure to monitor adverse reactions, the Committee seeks heightened surveillance following product licensing. It sees a need for a probationary period for the drug after it initially is approved and put on the market. This measure could provide outcomes similar to a phase four clinical trial.
The Committee recommends that:
· Health Canada make licensing of new drugs probationary to ensure that post-market surveillance of adverse drug reactions is carried out diligently during a specified period after the drug is approved for marketing;
· Health Canada increase resources for post-market surveillance so that the infrastructure has the capacity to receive, analyze and respond to consumer and health professional reports and complaints about adverse drug reactions;
· Health Canada increase resources dedicated to public disclosure of adverse drug reaction reports;
· Health Canada facilitate reporting by health care professionals using simple formats and integrated computer technologies that permit health providers to submit adverse drug reaction reports online;
· Health Canada facilitate adverse drug reaction reporting by consumers, including recognition of anecdotal evidence; and,
· Health Canada initiate work with its provincial and territorial counterparts to implement an effective mandatory reporting system for health care professionals.
What we heard
Within Health Canada, the Health Products and Food Branch administers the current regulatory framework that governs all health product advertising. The Food and Drugs Act and its regulations specify that direct-to-consumer advertising is substantially prohibited. However, advertising directed at health care professionals is permitted.
The prohibition on advertising directed at consumers applies to those drugs covered by Schedule A and Schedule F of the regulations. Schedule A lists 40 conditions and disorders for which treatments, preventions or cures cannot be advertised to the general public, while Schedule F includes chemical entities or classes of drugs which are required by regulation to be sold under prescription.
According to Health Canada, a complete prohibition against direct‑to‑consumer advertising of prescription drugs was inserted into the regulations in 1949 to protect the purchasing consumer against injury to health and against deception. In 1978, an amendment intended to accommodate price comparisons for consumers permitted prescription drug information for the public to include name, price and quantity.
Witnesses referred to two types of prescription drug messages considered permissible for public dissemination to consumers: reminder ads and help-seeking messages. Reminder ads may contain the name, price, and quantity of a particular drug but may not mention the disease or ailment that the drug is intended to treat. In practice, reminder ads tend to limit themselves to the name of the drug with some kind of lifestyle image, but price and quantity can be mentioned. Help‑seeking messages describe ailments or conditions and encourage consumers to talk to their doctor or their health care professionals about the different available treatments. Help-seeking messages cannot contain the name of the drug that the advertiser would like the doctor to recommend. Therefore, only reminder ads contain information about a specific prescription drug.
Witnesses cited research indicating that public exposure to direct‑to‑consumer advertising resulted in an increase in the use of prescription drugs and a greater tendency for doctors to prescribe what the patient requests. In addition, witnesses suggested that the advertising emphasis on newer expensive drugs leads to increased health care costs. They pointed out that health information and drug information must not be confused with advertising information aimed at selling a product. They acknowledged that the Canadian public can use accurate, up‑to‑date, comparative information on available treatment options, both drug and non-drug, for various conditions. However, they emphasized that the information should be publicly financed, produced and distributed because Canadians want assurances that the information is prepared independently of commercial interests.
At present, Health Canada is responsible for enforcing the regulations and addressing any complaints about prescription drug advertising and information intended for the Canadian consumer. Two voluntary organizations also have been endorsed by Health Canada to play a role in reviewing other advertising material on drugs. The Pharmaceutical Advertising Advisory Board oversees prescription drug advertisements permitted for health professionals and Advertising Standards Canada oversees the advertisement of non-prescription drugs to the general public. Although Health Canada provides a toll-free line and other mechanisms, both these non-governmental organizations occasionally receive complaints about prescription drug advertising directed at consumers. When complaints were forwarded to Health Canada, witnesses reported that they received no feedback from the Department on actions taken.
With respect to enforcement of the current regulations and policies on direct-to-consumer advertising, Health Canada indicated that its efforts range from education and voluntary compliance to warning letters and prosecution that could result in fines, injunctions or imprisonment. When the Health Products and Food Branch Inspectorate investigates complaints against advertisements, it does not proceed unless it can demonstrate that the ad is deceptive or poses significant risk to the health of Canadians. Witnesses suggested that no penalties have been imposed since 1978.
What we think
The Health Committee is concerned about the rising cost of health care in Canada and about the role of drug expenditures as a significant factor. It is convinced by research evidence suggesting that direct-to-consumer advertising of prescription drugs contributes to these costs.
The Committee heard that Health Canada, as part of its review of health protection legislation, is currently discussing the possibility of legislative changes to allow wider public advertising of prescription drugs. It agrees that the Canadian public can use high-quality, balanced information to assist in making informed decisions about prescription drug use. However, it wants the information to be provided by sources that do not benefit from product sales. In addition to governmental sources, such information could be prepared by various health organizations. The Committee feels strongly that, for all information on prescription drugs designated for the general public, Health Canada needs to take an active role in pre-clearance, surveillance and enforcement.
The Committee agrees with the original rationale for the prohibition against direct-to-consumer advertising of prescription drugs as protection against injury to health. It is of the opinion that drug advertisements could endanger rather than empower consumers by minimizing risk information and exaggerating benefits. The Committee contends that any direct-to-consumer advertising, including reminder ads, could contribute to increased or inappropriate drug consumption. Further, the Committee feels that the rationale for the 1978 amendment to the prohibition is no longer valid. Price comparison is no longer a significant issue for consumers as the majority of Canadians belong to some form of drug plan, whether publicly funded or through work or private insurance.
The Committee is concerned that the voluntary approach to pre-clearance of prescription drug advertisements with the burden for submitting complaints placed on the consumer is a feeble mechanism. Finally, the Committee is very dissatisfied with Health Canada’s passive stance on the enforcement of the current regulations about direct-to-consumer advertising. It feels that Health Canada has abrogated its clear responsibility to enforce the existing rules.
The Committee has multiple concerns about direct-to-consumer advertising of prescription drugs. It feels that such advertising contributes to increased health care costs; does not provide balanced and unbiased information; is potentially harmful to consumers; and has no ongoing scrutiny. The Committee therefore seeks strict measures to ensure that the existing prohibition is actively enforced.
The Committee recommends that:
· Health Canada immediately enforce the current prohibition of all industry-sponsored advertisements on prescription drugs to the public;
· Health Canada ensure the provision of independent, unbiased and publicly financed information on prescription drugs to Canadians;
· Health Canada dedicate specific resources to the Health Products and Food Branch Inspectorate for vigorous enforcement of the direct-to-consumer advertising regulations on prescription drugs, including active surveillance of all relevant media, identification of potential infractions, appropriate corrective action, and production of annual public reports;
· Health Canada ensure that all direct-to-consumer advertising complaints about prescription drugs received by Advertising Standards Canada or the Pharmaceutical Advertising Advisory Board are forwarded to Health Canada for investigation and action.